Abstract 5879: Effect of Minnelide, a prodrug, on cervical cancer growth

Abstract

Human Papilloma Virus (HPV) infection is associated with the development of Cervical cancer. Therapeutic resistance and recurrence remain the major obstacle to successful treatment of cervical cancer patients. Recently, a novel pro-drug Minnelide, derived from the diterpenoid triepoxide, triptolide, was found to be very effective against several human cancers in experimental animal models. The goal of the present study is to determine the effect of triptolide (in vitro) or Minnelide (in vivo) on HPV positive cervical cancer cells. Triptolide inhibited the proliferation of human cervical cancer cell lines, Ca Ski, SiHa, Me-180, and C-33a with an IC50 of 50 - 100 nM. Furthermore, triptolide inhibited the expression of viral oncoproteins E6 and E7 transcripts significantly. Consequently, p53, tumor suppressor protein levels were increased in the treated cells which led to increased apoptosis and reduced proliferation. Subsequently, we determined the effect of Minnelide on cervical cancer growth in athymic, nude mice. Tumor (SiHa and CaSki) bearing mice were treated with either 0.2 or 0.4 ug/kg doses of Minnelide. These studies showed that Minnelide inhibited tumor growth by about 70 % when compared to control group of mice and improved survival significantly. In a parallel study, combination treatment with carboplatin and Minnelide showed more than additive inhibition of tumor growth. In summary, Minnelide treatment reduced the transcript levels of HPV oncoproteins and inhibited cellular proliferation by upregulating p53. Our studies further demonstrate that Minnelide can be used either as a monotherapy or in combination with platinum drugs to inhibit the growth of cervical cancers. Citation Format: Vivek Ramakrishnan, Bhuwan Giri, Urvashi Hooda, Peter Wilkinson, Christopher deHaydu, Janneth Oleas, Sabita Roy, Sundaram Ramakrishnan, Ashok Saluja. Effect of Minnelide, a prodrug, on cervical cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5879.

Minnelide Markedly Reduces Proteinuria in Mice with Adriamycin Nephropathy by Protecting Against Podocyte Injury

“…For male mice, 400 μg/kg/d could increase germ cell degeneration and exfoliation in testes, but both 100 and 200 μg/kg/d had no significant effect on testes after treatment with minnelide for 2 weeks. Previous studies demonstrated that 200 μg/kg/d minnelide treatment for 5 weeks had no significant effect on the body weight of mice [45], and 0.21 μg/kg/d minnelide treatment for 2 weeks did not affect the blood indexes of mice [19]. Meanwhile, Minneamrita Therapeutics LLC initiated many clinical trials (NCT01927965, NCT03117920, NCT03129139, and NCT03760523) for minnelide [47].…”

“…Therefore, the researchers have processed the triptolide to produce minnelide [8]. Minnelide is a water-soluble prodrug of triptolide, which has shown significant therapeutic effects against a large number of cancers in preclinical studies [2,23,35,45]. In the body, minnelide is rapidly converted into triptolide in the presence of alkaline phosphatase [8].…”

Triptolide and its prodrug Minnelide target high-risk MYC-amplified medulloblastoma in preclinical models

“…Given the rapid conversion of Minnelide into active triptolide in vivo (12) and its documented accumulation in brain tissues (30), we next assessed the efficacy of Minnelide in orthotopic mouse MB models. Minnelide was administered in these experiments at previously reported dosages (12,(32)(33)(34)(35). Mice orthotopically implanted with luciferase-expressing G3 MB cells (HD:MB03) were exposed to vehicle or Minnelide.…”

“…While Minnelide and triptolide demonstrated similar EC50s ex vivo, differences in in vivo efficacy were noted. These variations could arise in part from the administration of a lower effective dose of Minnelide, though the regimen used was supported by previous Minnelide pre-clinical studies (12,(32)(33)(34)(35). Due to differences in molecular weights, 0.7 molar equivalents of Minnelide were administered relative to triptolide when 0.4 mg/kg dose levels were administered for each agent.…”

Increased human papillomavirus viral load is correlated to higher severity of cervical disease and poorer clinical outcome: A systematic review

“…These events are crucial for progression from high-grade premalignant lesions to cervical cancer. [37][38][39][40][41]…”